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J. Biol. Chem., Vol. 281, Issue 20, 13957-13963, May 19, 2006

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Hypoxic Regulation of Vascular Endothelial Growth Factor through the Induction of Phosphatidylinositol 3-Kinase/Rho/ROCK and c-Myc^*

From the Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

The induction of vascular endothelial growth factor (VEGF) is an essential feature of tumor angiogenesis. Hypoxia is a potent stimulator of VEGF expression, and hypoxia-inducible factor-1 (HIF-1) is considered to be critical for this induction. However, we have previously demonstrated that induction of VEGF by hypoxia was preserved when HIF-1 was silenced. We sought to better define the molecular basis of this HIF-1-independent regulation. In colon cancer cells, hypoxia stimulated multiple K-ras effector pathways including phosphatidylinositol 3-kinase. VEGF promoter deletion studies identified a novel promoter region between –418 and –223 bp that was responsive to hypoxia in a PI3K/Rho/ROCK-dependent manner. Electrophoretic mobility shift assays identified a fragment between –300 and –251 bp that demonstrated a unique shift only in hypoxic conditions. Inhibition of PI3K or ROCK blocked the formation of this complex. A binding site for c-Myc, a target of ROCK, was identified at –271 bp. A role for c-Myc in the hypoxic induction of VEGF was demonstrated by site-directed mutagenesis of the VEGF promoter and silencing of c-Myc by small interfering RNA. Collectively, these findings suggest an alternative mechanism for the hypoxic induction of VEGF in colon cancer that does not depend upon HIF-1 but instead requires the activation of PI3K/Rho/ROCK and c-Myc.

Received for publication, November 1, 2005 , and in revised form, February 7, 2006.

^* This work was supported by National Institutes of Health Grant CA92594 (to D. C. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ Recipient of a postdoctoral fellowship award from the Deutsche Forschungsgemeinschaft.

² Recipient of an American Gastroenterology Association Student Research fellowship.

³ To whom correspondence should be addressed: Gastrointestinal Unit, GRJ-825, MA General Hospital, 55 Fruit St., Boston, MA 02114. Tel.: 617-726-8687; Fax: 617-726-5895; E-mail: chung.daniel{at}mgh.harvard.edu.

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